Patent GB-580884-A (GB)
Title: Improvements in and relating to therapeutically active compounds of the amidine type
Filed: 1944-01-26
Abstract: Amidine compounds having antibacterial activity, in which the guanyl residue is attached to an aromatic nucleus carrying in the paraposition with respect to the guanyl residue a sulphone radical, -SO2R, wherein R represents an aliphatic or substituted aliphatic residue, are obtained by treating the corresponding precursor nitrile compounds at a low temperature with hydrogen chloride or hydrogen bromide and treating the resultant imino-ether hydrohalide with ammonia.  Specified amidine salts are the hydrochlorides of benzamidine-p-methylsulphone, benzamidine-p-ethylsulphone, benzamidine-p-n-propylsulphone, benzamidine-p-benzylsulphone and benzamidine-p-acetonyl-sulphone, the dihydrochloride of benzamidine-p-guanylsulphone and the benzoate of benzamidine-p-n-butylsulphone, formed by double decomposition of the hydrochloride with concentrated aqueous odium benzoate.  The nitriles used as starting-materials may be obtained: (a) by treatment of the corresponding aromatic primary amines by the Sandmeyer reaction or its known variants, especially that in which a nickel salt is employed as a "promoter," or (b) from a salt of p-cyanobenzenesulphinic acid, by reaction with an alkylating, or aralkylating, agent.  In examples: (1) benzonitrile-p-methylsulphone, suspended in a mixture of dry absolute alcohol and chloroform, is saturated with dry hydrogen chloride at 0 DEG  C. and the preparation is refrigerated for 4-7 days with daily agitation prior to removing the excess of hydrogen chloride and solvent in vacuo at 25 DEG  C. to deposit the imino-ether hydrochloride, which is then charged in a pressure vessel with 10 per cent alcoholic ammonia for 4-6 days at 37 DEG  C. to yield a mixture of the amidine hydrochloride, free amidine and ammonium chloride, further crops being obtained from the filtrate.  The impure product is suspended in water acidified to pH 4-5 with 2N. hydrochloric acid and the solution is processed to yield successive crops of crude benzamidine-p-methylsulphone hydrochloride (2) p-cyanobenzenesulphonylacetonitrile, suspended in absolute alcohol and chloroform, is saturated with hydrogen chloride at 0 DEG C. and treated as in (1), digesting at 37 DEG  C. with saturated alcoholic ammonia for 7 days, and ultimately processing the product as in (1) to isolate benzamidine-p guanylmethylsulphone dihydrochloride.  Benzonitrile-p-methylsulphone is obtained by diazotizing p - aminobenzene methylsulphone hydrochloride with aqueous sodium nitrite and pouring the product into an aqueous solution containing sodium cyanide and hydrated nickel chloride which is stirred and heated in a boiling water-bath, maintaining the temperature for 10-15 mins. after addition of the diazosolution, the crude solid being dissolved in acetone, filtered and recrystallised from water, using norite.  p - Cyanobenzenesulphonylacetonitrile is obtained by refluxing sodium p-cyanobenzenesulphinate and chloroacetonitrile in aqueous alcohol for 12 hours, followed by removal of solvent and excess of chloroacetonitrile in vacuo, and subsequent isolation of the product as crystals on adding water. p-Cyanobenzenesulphinic acid is obtained by reducing p - cyanobenzenesulphonyl chloride with sodium sulphite.